Donex orodispersible tablets 5 mg No. 30

Instructions for Donex orally dispersible tablets 5 mg No. 30

Composition

The active ingredient is donepezil hydrochloride;

1 tablet contains donepezil hydrochloride 5 mg or 10 mg;

Excipients: polacrilin potassium; microcrystalline cellulose; lactose monohydrate; monosodium citrate anhydrous; aspartame (E 951); croscarmellose sodium; colloidal anhydrous silica; magnesium stearate

Dosage form

Orodispersible tablets

Main physicochemical properties

5 mg tablets are round, flat, beveled edged tablets from white to almost white in color, embossed with "5" on one side and smooth on the other side;

10 mg tablets: round, flat, bevelled edged tablets, white to off-white, debossed with "10" on one side and plain on the other side

Pharmacotherapeutic group

Drugs used in dementia Cholinesterase inhibitors ATX code N06D A02

Pharmacological properties

Pharmacodynamics

Mechanism of action

Donepezil hydrochloride is a specific reversible inhibitor of acetylcholinesterase, which is the major type of cholinesterase in the brain. In vitro, donepezil hydrochloride has been shown to be 1000 times more potent at inhibiting the activity of this enzyme than its ability to inhibit butyrylcholinesterase, which is predominantly located outside the central nervous system (CNS).

Alzheimer's dementia

It is known that in patients with Alzheimer's disease who participated in clinical studies, the administration of donepezil at a dose of 5 mg or 10 mg 1 time per day after reaching equilibrium concentration resulted in inhibition of acetylcholinesterase activity (which was determined in the cell membrane of erythrocytes) by 63.6% and 77.3%, respectively. It has been shown that the inhibition of acetylcholinesterase in erythrocytes by donepezil hydrochloride correlated with changes in the ADAS-cog score (Alzheimer's Disease Assessment Scale for Cognitive Function), which allows to test some aspects of cognitive function.

The efficacy of donepezil treatment was studied in four placebo-controlled trials, two of 6-month duration and two of 1-year duration.

It is known that in a 6-month clinical study, the effectiveness of donepezil treatment was analyzed based on a combination of three criteria: the number of points on the ADAS-Cog scale (an indicator of cognitive function), the number of points on the scale for assessing the patient's condition by a doctor or caregivers (the CIBIC+ scale, an indicator of general function), and the number of points on the subscale for assessing daily activities with clinical signs of dementia (an indicator of the ability to perform social activities, housework, favorite activities, and self-care)

Patients who meet the criteria below will be considered to have responded to treatment.

Response: improvement in the ADAS-Cog score by at least 4 points, no deterioration in the CIBIC+ score, no deterioration in the subscale for assessing daily activities with clinical signs of dementia

*p

**p

Donepezil caused a dose-dependent statistically significant increase in the relative number of patients who responded to treatment.

Pharmacokinetics

Absorption

After oral administration, the maximum plasma concentration Cmax is reached after approximately 3–4 hours. Plasma concentration and area under the concentration-time curve (AUC) increase in proportion to the dose. The terminal half-life is approximately 70 hours, so multiple once-daily administration results in a gradual achievement of steady-state concentrations. Steady-state concentrations are reached approximately within 3 weeks of initiation of treatment. Once steady-state is reached, donepezil hydrochloride concentrations and the associated pharmacodynamic activity remain almost constant throughout the day.

Food does not affect the absorption of donepezil hydrochloride.

Distribution

Approximately 95% of donepezil hydrochloride is bound to plasma proteins. The extent of plasma protein binding of the active metabolite 6-O-desmethyldonepezil is unknown. The distribution of donepezil hydrochloride in various body tissues has not been studied in detail. However, a mass balance study in healthy male volunteers showed that approximately 28% of the label remained unrecovered 240 hours after a single administration of 5 mg of 14C-labeled donepezil hydrochloride. This suggests that donepezil hydrochloride and/or its metabolites may persist in the body for more than 10 days.

Donepezil hydrochloride can be excreted unchanged in the urine or metabolized in the liver by cytochrome P450 isoenzymes to form many metabolites, not all of which have been identified. After a single administration of 5 mg of 14C-labeled donepezil hydrochloride, plasma radioactivity, expressed as a percentage of the administered dose, was mainly due to intact donepezil hydrochloride (30%), 6-O-desmethyldonepezil (11%, the only metabolite that exhibits the same activity as donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyldonepezil (7%) and the glucuronide conjugate of 5-O-desmethyl-donepezil (3%). Approximately 57% of the total administered radioactivity was recovered in urine (17% as unchanged donepezil) and 14.5% was recovered in feces, indicating that biotransformation and urinary excretion are the major routes of elimination. There was no evidence of enterohepatic recirculation of donepezil hydrochloride and/or any of its metabolites.

The decrease in plasma concentrations of donepezil occurs with a half-life of approximately 70 hours.

Gender, race, and smoking history had no clinically significant effect on plasma concentrations of donepezil hydrochloride. The pharmacokinetics of donepezil have not been formally studied in healthy elderly volunteers or in patients with Alzheimer's disease or vascular dementia. However, mean plasma concentrations were similar in patients and in young healthy volunteers.

In patients with mild to moderate hepatic impairment, steady-state concentrations of donepezil were increased, with AUC increasing by 48% and mean Cmax increasing by 39% (see section 4.2).

Indication

The drug Donex®, orodispersible tablets, is indicated for the symptomatic treatment of mild to moderate Alzheimer's dementia.

Contraindication

Hypersensitivity to donepezil hydrochloride, piperidine derivatives or to any of the excipients of the drug.

Interaction with other medicinal products and other types of interactions

Donepezil hydrochloride and/or any of its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine or digoxin in humans. Concomitant administration of digoxin or cimetidine does not affect the metabolism of donepezil hydrochloride. In vitro studies have shown that cytochrome P450 isoenzymes, in particular isoenzyme 3A4 and to a lesser extent isoenzyme 2D6, are actively involved in the metabolism of donepezil. In vitro drug interaction studies have shown that ketoconazole and quinidine, which are inhibitors of CYP3A4 and 2D6, respectively, inhibit the metabolism of donepezil. Therefore, these and other inhibitors of the CYP3A4 isoenzyme, such as itraconazole and erythromycin, as well as inhibitors of the CYP2D6 isoenzyme, such as fluoxetine, may inhibit the metabolism of donepezil. In a study involving In healthy volunteers, ketoconazole increased the average concentration of donepezil in the blood by approximately 30%. Enzyme inducers, such as rifampicin, phenytoin, carbamazepine and alcohol, may reduce the concentration of donepezil in the blood. The degree of inducing or inhibiting action remains unknown, so such combinations of drugs should be used with caution. Donepezil hydrochloride may affect drugs with anticholinergic activity, reducing their effect. Synergistic activity may occur when Donex® is taken simultaneously with succinylcholine, other muscle relaxants, cholinergic agonists or beta-blockers that affect cardiac conduction. Thus, the simultaneous use of Donex® with muscle relaxants of depolarizing action may lead to excessive relaxation of skeletal muscles, which is especially dangerous due to respiratory arrest, due to excessive relaxation of the respiratory muscles. Simultaneous use of Donex® with with cholinomimetic drugs may cause severe nausea, vomiting, salivation, increased sweating, decreased heart rate, decreased blood pressure, respiratory depression, convulsions. Simultaneous use of the drug Donex® with beta-blockers may significantly reduce the strength and frequency of heart contractions and lead to depression of the cardiac conduction system (see section "Special instructions for use")

Cases of QTc prolongation and torsade de pointes have been reported with donepezil. Caution is advised when using donepezil concomitantly with other medicinal products that prolong the QTc interval; clinical monitoring (ECG) may be necessary. Examples of such medicinal products are listed below.

- class IA antiarrhythmics (e.g. quinidine);

- class III antiarrhythmics (e.g. amiodarone, sotalol);

- some antidepressants (e.g. citalopram, escitalopram, amitriptyline);

- other antipsychotics (e.g. phenothiazine derivatives, sertindole, pimozide, ziprasidone);

- some antibiotics (e.g. clarithromycin, erythromycin, levofloxacin, moxifloxacin)

Application features

The use of donepezil in dementia in patients with severe Alzheimer's disease, other types of dementia, or other types of memory impairment (e.g., age-related cognitive decline) has not been studied.

Anesthesia Donepezil, as a cholinesterase inhibitor, may enhance muscle relaxation when depolarizing muscle relaxants (succinylcholine type) are used during anesthesia.

Cardiovascular disorders Cholinesterase inhibitors, due to their pharmacological action, may have a vagotonic effect on heart rate (e.g., cause bradycardia). This effect may be of particular importance in patients with sick sinus syndrome or other supraventricular conduction disorders, such as sinoatrial or atrioventricular block.

Cases of syncope and seizures have been reported. When examining such patients, special attention should be paid to the state of the cardiac conduction system and the possibility of conduction block or long sinus node pauses should be considered.

QTc prolongation and torsade de pointes have been reported in the post-marketing setting (see sections 4.5 and 4.8).

Caution is recommended in patients with a history of QTc prolongation or a family history of QTc prolongation, in patients taking medications that affect the QTc interval, in patients with cardiac disease (e.g., decompensated heart failure, recent myocardial infarction, bradyarrhythmia) or electrolyte disturbances (hypokalemia, hypomagnesemia). Clinical monitoring (ECG) may be required.

Gastrointestinal disorders: Patients at increased risk of developing ulcers should be closely monitored for gastrointestinal symptoms, particularly those with a history of peptic ulcer disease or those taking nonsteroidal anti-inflammatory drugs. However, in clinical trials with donepezil, there was no increase in the incidence of gastric and duodenal ulcers or gastrointestinal bleeding compared to placebo.

Genitourinary disorders Cholinomimetics may cause urinary outflow disorders, although such disorders were not observed in clinical studies with donepezil.

Neurological disorders Epileptic seizures Cholinomimetics are believed to have the ability to cause generalized seizures However, such seizures can also be a manifestation of Alzheimer's disease itself

Cholinomimetics have the potential to exacerbate or cause extrapyramidal disorders.

Neuroleptic malignant syndrome (NMS)

There are very few reports of donepezil-induced NMS, particularly in patients taking neuroleptics concomitantly. NMS is a life-threatening condition characterized by hyperthermia, muscle rigidity, autonomic nervous system disorders, impaired consciousness, and elevated serum creatinine and phosphokinase levels. NMS may be complicated by myoglobinuria (rhabdomyolysis) and acute renal failure. Treatment should be discontinued if the patient develops signs and symptoms suggestive of NMS, or if a high fever of unexplained etiology occurs without additional clinical manifestations.

Pulmonary diseases: Cholinesterase inhibitors, due to their cholinomimetic effects, should be prescribed with caution to patients with a history of bronchial asthma or chronic obstructive pulmonary disease.

Donepezil is not recommended for use with other acetylcholinesterase inhibitors, agonists or antagonists of the cholinergic system.

Mortality in clinical trials in patients with vascular dementia: It is known that 3 clinical trials of 6 months duration were conducted in patients who met the NINDS-AIREN criteria for probable or possible vascular dementia. The NINDS-AIREN criteria were designed to identify patients whose dementia may be due exclusively to vascular causes and to exclude patients with Alzheimer's disease. In the first study, the incidence of fatal events was 2/198 (1%) with donepezil hydrochloride 5 mg, 5/206 (2.4%) with donepezil hydrochloride 10 mg, and 7/199 (3.5%) with placebo. In the second study, the incidence of fatal events was 4/208 (1.9%) with donepezil hydrochloride 5 mg, 3/215 (1.4%) with donepezil hydrochloride 10 mg, and 7/199 (3.5%) with placebo. In the third study, the incidence of fatal events was 11/648 (1.7%) with donepezil hydrochloride 5 mg and 0/326 (0%) with placebo. In all three vascular dementia studies, the incidence of fatal events in the pooled donepezil hydrochloride group (1.7%) was quantitatively higher than in the placebo group (1.1%), but this difference was not statistically significant. The majority of deaths in patients taking either donepezil hydrochloride or placebo were due to various vascular causes, as would be expected in elderly patients with pre-existing vascular disease. When all serious non-fatal and fatal vascular events were analyzed, there was no difference in the incidence of these events between the donepezil hydrochloride and placebo groups.

In the Alzheimer's disease studies (n = 4146) and the pooled Alzheimer's disease and dementia studies, including vascular dementia studies (total n = 6888), the incidence of fatal events in the placebo groups was quantitatively higher than in the donepezil hydrochloride groups.

Precautions regarding auxiliary ingredients

The composition of the drug Donex® includes lactose, therefore it is not recommended for use in patients with rare hereditary and acquired disorders such as fructose or galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome or sucrase-isomaltase deficiency.

The drug contains aspartame, a derivative of phenylalanine, which is dangerous for patients with phenylketonuria.

Use during pregnancy or breastfeeding

Pregnancy

There are no adequate data from the use of donepezil in pregnant women.

It is known that in animal experiments no teratogenic effect was observed, but signs of toxicity occurred in the peri- and postnatal period. The potential risk for humans remains unknown.

Donepezil is not recommended for use during pregnancy unless clearly necessary.

Breastfeeding period

Donepezil is known to be excreted in rat milk. Studies in lactating women have not been conducted, so it is unknown whether donepezil hydrochloride is excreted in human milk. Therefore, women should discontinue breastfeeding during treatment with donepezil.

Ability to influence reaction speed when driving vehicles or other mechanisms

Since donepezil may cause fatigue, dizziness, muscle cramps, especially at the beginning of treatment or when the dose is increased, it may have minor or moderate adverse effects on the ability to drive and use machines.

At the same time, dementia may also cause a deterioration in the patient's ability to drive a car and other mechanical devices. Accordingly, the physician should regularly assess the patient's ability to drive a car or use complex mechanical devices during treatment with donepezil.

Method of administration and doses

Adults/elderly

Treatment should be started at a dose of 5 mg once daily.

The 5 mg daily dose should be administered for at least 1 month to assess early clinical response to treatment and to achieve steady-state plasma concentrations of donepezil. After clinical evaluation of treatment at 5 mg daily for 1 month, the dose may be increased to 10 mg once daily. The maximum recommended daily dose is 10 mg. Doses greater than 10 mg daily have not been studied in clinical trials.

Treatment should be initiated and continued under the supervision of a physician experienced in the diagnosis and management of Alzheimer's dementia. The diagnosis should be made in accordance with generally accepted guidelines. Treatment with donepezil should only be initiated if the patient has a caregiver who will regularly monitor the patient's intake of this medication. Supportive treatment should be continued as long as the patient is showing a therapeutic effect. Therefore, the clinical benefit of donepezil treatment should be reassessed regularly. Treatment should be discontinued when the therapeutic effect is no longer observed. Individual response to donepezil cannot be predicted.

Kidney and liver dysfunction

The same dosing regimen can be used in patients with renal impairment, as this impairment does not affect the clearance of donepezil hydrochloride.

Due to possible increased systemic exposure in mild to moderate hepatic impairment (see section 5.2), the dose should be increased based on individual tolerability. There are no data available for patients with significant hepatic impairment.

Method of administration and doses

The drug Donex® should be taken orally in the evening, before bedtime. The tablet should be placed on the tongue and allowed to disintegrate before swallowing with or without water, depending on the patient's preference.

Children

The drug Donex® is not recommended for use in children under 18 years of age.

Overdose

The lethal single oral dose of donepezil hydrochloride for mice and rats is known to be on average 45 and 32 mg/kg, respectively, which is approximately 225 and 160 times the maximum recommended human dose (10 mg/day). Dose-dependent signs of cholinergic stimulation were observed in animals, which included decreased spontaneous motor activity, prone position, unsteadiness of gait, lacrimation, clonic convulsions, respiratory depression, salivation, miosis, fasciculations, and decreased skin temperature.

Overdose of cholinesterase inhibitors can lead to cholinergic crisis, which is characterized by severe nausea, vomiting, salivation, increased sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Muscle weakness may occur, which can be fatal due to respiratory muscle failure.

As with any other drug overdose, general supportive measures should be taken. Tertiary anticholinergics, such as atropine, may be used as an antidote for donepezil overdose. Intravenous atropine sulfate is recommended, titrated to achieve a therapeutic effect. The initial dose is 1–2 mg intravenously, and subsequent doses should be titrated according to clinical response. Atypical blood pressure and heart rate responses have been reported with other cholinomimetics administered concomitantly with quaternary anticholinergics, such as glycopyrrolate. It is unknown whether donepezil hydrochloride and/or its metabolites are dialysable (hemodialysis, peritoneal dialysis, or hemofiltration).

Adverse reactions

The most common side effects are diarrhea, muscle cramps, fatigue, nausea, vomiting, and insomnia.

The frequency of the following adverse reactions is defined as very common (≥ 1/10), common (≥ 1/100 and

Infections and invasions are frequent – colds, runny noses;

Metabolism and digestion often - anorexia

Psychiatric disorders common – hallucinations**, agitation**, aggressive behavior**, sleep disorders, nightmares**, agitation

Nervous system disorders: Common: syncope*, dizziness, insomnia; uncommon: convulsions*; rare: extrapyramidal disorders; very rare: neuroleptic malignant syndrome (NMS)

Cardiac disorders: uncommon: bradycardia; rare: sinoatrial block, atrioventricular block; frequency unknown: polymorphic ventricular tachycardia, including torsade de pointes, prolongation of the QT interval on ECG

Gastrointestinal: very common: diarrhea, nausea; common: vomiting, abdominal discomfort; uncommon: gastrointestinal bleeding, gastric and duodenal ulcers, hypersalivation

Hepatobiliary disorders Rare – liver dysfunction including hepatitis***

Skin and subcutaneous tissue disorders: Common: rash, itching

Musculoskeletal and connective tissue disorders: Common: muscle cramps; very rare: rhabdomyolysis****

Kidney and urinary tract disorders: Common: urinary incontinence

Systemic disorders and reactions at the injection site very common - headache; common - fatigue, pain

Investigations uncommon – slight increase in serum muscle creatine kinase concentration

Injuries, poisonings and procedural complications are often accidental, including falls

* When examining patients with syncope or epileptic seizures, the possibility of conduction block or long sinus node pauses should be considered (see section "Special instructions for use")

** Hallucinations, agitation, and aggressive behavior have been reported to resolve after dose reduction or discontinuation of treatment

*** In cases of liver dysfunction of unknown cause, it is recommended to consider discontinuing donepezil.

**** Rhabdomyolysis has been reported to occur independently of ALS, with a clear temporal relationship to the initiation of donepezil treatment and dose escalation.

Expiration date

3 years

Storage conditions

Keep out of reach of children. No special storage conditions required.

Packaging

10 tablets in a blister; 3 or 6 blisters in a cardboard box

14 tablets in a blister; 2 blisters in a cardboard box

Vacation category

By prescription

Producer

Genepharm SA

18th km Marathonos Ave, Pallini Attica, 15351, Greece